Famciclovir for the Treatment of Recurrent Genital and Labial Herpes Lesions

Famciclovir (Famvir®, Novartis) is an effective treatment for herpes zoster and herpes simplex. Two separate studies recently examined the effectiveness of single high doses of famciclovir for treating recurrent genital herpes and labial herpes (cold sores). In the randomized, placebo-controlled studies, patients initiated treatment at the first onset of symptoms. For the treatment of genital herpes, a 1,000mg b.i.d. dose of famciclovir had significant advantages over the placebo, reducing the time required to heal the lesions, preventing the development of lesions beyond the papule stage, and improving the time to resolution of all symptoms. For the treatment of labial herpes, a single 1,500mg dose of famciclovir shortened the lesion healing time, shortened the time to normal skin, and resulted in faster resolution of pain and tenderness.

Key Words:
famciclovir, herpes zoster, herpes simplex

Infections with herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) are important, common, and worldwide in distribution. It has been estimated that 90% of individuals aged 20-40 years have antibodies to HSV-1, and HSV-2 is the most common sexually transmitted disease worldwide.1 HSV-1 is most frequently connected with orolabial herpes and HSV-2 with genital herpes, although either type can affect either location.
Infection with HSV can initially result in primary infection, followed by an establishment of latency as the viral genome remains in the neuronal bodies indefinitely. Patients may then have recurrences which may be symptomatic or asymptomatic.2 Certain patients can experience frequent recurrences which may be symptomatic, oral antivirals are the agents of choice in this setting.

Very recently, two clinical studies were completed in patients with recurrent labial and genital herpes using famciclovir. In this article these studies will be briefly reviewed and the implications identified.

Recurrent Genital Herpes

An international randomized, double-blind, multi-center, placebo-controlled study compared the effectiveness of a 1,000mg b.i.d. single-day dose of famciclovir with a placebo in patients with recurrent genital herpes (i.e., >4 episodes over 12 months).3

Three hundred twenty nine patients were randomized to receive famciclovir (n=163) or placebo (n=166). The patients in the treated and placebo arms were well-balanced in demographic and baseline disease characteristics. In this study, the major inclusion criteria were:

aged 18 years or older

history of recurrent genital herpes on the external genitalia or anogenital area, with four or more episodes in the previous 12 months.

HSV-2 seropositivity

if applicable, be willing to discontinue suppressive treatment.

Lesions requiring re-epithelialization were defined as lesions that underwent vesicular, ulcer, soft crust and/or hard crust formation. Aborted lesions were considered to be lesions that did not progress beyond the papule stage.

Efficacy Variables

The primary efficacy variable in the study was investigator-assessed time to healing of all nonaborted genital herpes lesions. Secondary efficacy variables included:

the safety and tolerability of a 1,000mg b.i.d. dose of famciclovir

the proportion of patients with aborted lesions

the time to resolution of all symptoms, including burning, pain, tingling, itching, and tenderness.

Patients initiated dosing within 6 hours of the first symptoms. Patients returned to the clinic within 24 hours, and then visited the clinic for 3 consecutive days. They returned every other day until the lesions were healed or until day 14, whichever came first.

Adverse Events

Just over one-quarter of patients receiving famciclovir (26.4%) reported adverse events, of which 12.9% were deemed by the investigator to be drug related. These included gastrointestinal disorders (such as diarrhea or nausea) and headaches. The side-effects were mild and transient in the majority of patients. Patients receiving the placebo also reported these adverse events.

Population

Famciclovir

Placebo

Hazard Ratio**

P

Modified ITT***

4.3 (3.9, 5.0)

6.1 (5.0, 7.0)

1.64

< 0.001

Per Protocol

4.3 (3.9, 5.5)

6.2 (5.3, 7.4)

1.72

0.009

Table 1: Time to healing (days)* of non-aborted lesions.*Median time to healing and 95% CI for the median time are shown.**Based on proportional hazards model with treatment, center and gender as explanatory variables.***ITT = Intent to treat.

Table 3: Time to resolution (days)* of symptoms in the ITT population**Median time to healing and 95% CI for the median time are shown.**Based on proportional hazards model with treatment, center and gender as explanatory variables.

Conclusions

Two 1,000mg doses of famciclovir over a single day, started within 6 hours of prodromal symptoms or genital herpes lesions, were shown to:

be well tolerated and safe

play a significant role in reducing the time to healing of vesicular lesions

significantly prevent the development or progression of lesions beyond the papule stage

significantly improve the time to resolution of all symptoms, including burning, tingling, itching, and tenderness.

Treatment

n

Median time to
resolution (days)

Hazard Ratio*,**
95% CI)

P

Famciclovir, 1,500mg,
single dose

152

4.4

1.64 (1.26-2.14)***

< 0.001***

Famciclovir, 750mg
b.i.d., single day

157

4.0

2.05 (1.58-2.66)****

0.001****

Placebo

168

6.2

Table 4: Time to healing of primary vesicular lesions* Based on the SAS PROC LIFETEST (Brookmeyer-Crowley method).** Based on proportional hazards model with treatment, center, and gender as explanatory variables.*** Famciclovir 1,500mg single dose versus placebo.**** Famciclovir 750mg b.i.d., single day, versus placebo.

Treatment

n

Median time to
resolution (days)

Hazard Ratio*,**
95% CI)

P

Famciclovir, 1,500mg,
single dose

152

4.5

1.71 (1.31-2.22)***

< 0.001***

Famciclovir, 750mg
b.i.d., single day

157

4.1

2.06 (1.59-2.68)****

0.001****

Placebo

168

6.6

Table 5: Time to healing of all vesicular lesions* Based on the SAS PROC LIFETEST (Brookmeyer-Crowley method).** Based on proportional hazards model with treatment, center, and gender as explanatory variables.*** Famciclovir 1,500mg single dose versus placebo.**** Famciclovir 750mg b.i.d., single day, versus placebo.

Treatment

n

Median time to
resolution (days)

Hazard Ratio*,**
95% CI)

P

Famciclovir, 1,500mg,
single dose

227

4.5

1.50 (1.18-1.90)***

< 0.001***

Famciclovir, 750mg
b.i.d., single day

220

5.7

1.26 (0.98-1.62)****

0.067****

Placebo

254

7.0

Table 6: Time to return to normal skin* Based on the SAS PROC LIFETEST (Brookmeyer-Crowley method).** Based on proportional hazards model with treatment, center, and gender as explanatory variables.*** Famciclovir 1,500mg single dose versus placebo.**** Famciclovir 750mg b.i.d., single day, versus placebo.

A single-day patient-initiated regimen is convenient and has the advantage of maximizing the window of opportunity for treatment when viral replication is most active. Famciclovir was shown to stop the progression to a full outbreak or shorten the duration of a recurrent genital herpes outbreak.

Recurrent Herpes Labialis

A randomized, double-blind, parallel group, placebo-controlled study examined the effectiveness of a single 1,500mg dose of famciclovir, two 750mg doses of famciclovir over a single day, and a matching placebo.4 Patients initiated therapy within 1 hour of prodromal symptoms. Patients returned to the clinic within 24 hours, and then visited the clinic for the 3 following consecutive days. After that they returned every other day until the lesions were healed or until day 14, whichever came first.

The 708 patients in the study population were adult immunocompetent patients with recurrent cold sores. The mean age was approximately 39 years, with the majority of patients being female and Caucasian.
The study also examined the time to resolution of pain and tenderness. The median time to resolution was 1.7 days for those who received the 1,500mg dose of famciclovir, 2.1 days for those receiving two 750mg doses of famciclovir over a single day, and 2.9 days for those who received the placebo.

Conclusions

A single dose of famciclovir (1,500mg) taken within the first hour of prodromal symptoms resulted in the following statistically significant differences as compared with a placebo:

shorter time to healing of vesicular herpes labialis lesions by approximately 2 days

shorter time to resolution to normal skin by approximately 2 days

Faster resolution of pain and tenderness by approximately 1 day.

The advantage of a single-dose, patient-initiated regimen is that it maximizes the window of opportunity for treatment when viral replication is the most active. A single dose can provide all the therapy up-front.

This study shows that a single dose (1,500mg) of famciclovir is effective in treating a herpes labialis outbreak, is well tolerated, and is convenient - a factor that may have the potential to improve patient compliance.